Diabetic patients with overt neuropathy exhibit asymptomatic abnormalities of esophageal motor function. Previously reported abnormal findings include frequent non-peristaltic contractions, delayed clearance and decreased lower esophageal sphincter (LES) pressure. We have noted an esophageal manometric aberration in diabetic patients with neuropathy that has not been described previously. Fourteen insulin-dependent diabetics (age 21–64 yrs) with peripheral and autonomic neuropathy were investigated. None had esophageal symptoms, but 6 complained of vomiting, 5 had diarrhea and 3 had both. Gastric emptying of a radiolabelled solid meal was abnormal in 11 of 14. Small bowel manometric findings were abnormal in the 5 patients with diarrhea. Control subjects included 6 diabetic patients without neuropathy (16–64 yrs), 100 consecutive non-diabetic patients evaluated for suspected esophageal disease and 30 healthy volunteers (18–32 yrs). We used a multilumen manometric tube that featured an orifice for measuring gastric pressure, a sleeve device for measuring LES pressure and 6 orifices spaced at 3-cm intervals for recording pressure activity in the esophageal body. Each lumen was perfused with distilled water (0.5 ml/min) by a minimally compliant hydraulic system. Three rapid pull-throughs across the LES were performed using the 4 recording sites above the sleeve. The sleeve was then positioned straddling the LES. Esophageal responses were recorded for 10 wet swallows (5 ml H20), at intervals of 30 seconds, under basal conditions, after amyl nitrite, edrophonium (80 ug/kg IV) and atropine (3 ug/kg IV). Results: Resting LESP (22.5 ± 6 SD mm/Hg) and LES relaxation were normal. The incidence of complete primary peristalsis was normal (>80%) in 12 patients. Two patients had 50–80% failed swallows. Thirteen patients exhibited a singular manometric aberration of multiphasic peristaltic pressure waves in the smooth-muscle esophagus. These complexes usually had a “rabbit-ear”, double-peaked profile, but in some cases had several peaks. Peak amplitudes ranged from 40–200 mmHg. Propagation measured from onset of the multiphasic pressure complex or from the initial pressure peak was normal. Concurrent fluroscopic and manometric monitoring demonstrated that the multiphasic wave complexes stripped barium from the smooth-muscle esophageal segment in a normal fashion. The second wave of the multiphasic wave complex was simultaneous at two or more sites in 34%, appeared retrograde in 4% and was antigrade in 62%. Edrophonium (80 ug/kg IV) increased the number and amplitude of the phasic waves, whereas atropine (3 ug/kg IV) reduced the number and amplitude, often to a single-peaked peristaltic complex. Only 2 subjects in the control groups demonstrated multiphasic peristaltic pressure complexes phenomenon. We conclude: 1) Most of our diabetics with neuropathy (13/14) had multiphasic esophageal peristaltic pressure complexes with normal bolus transport. 2) Although the underlying cause of this aberration remains to be determined, increased cholinergic sensitivity appears to play a role.